Encouraging Trends in Six-Month Mortality in Amyloid Light-Chain Amyloidosis

With recent advances in diagnosis, treatment, and response assessment, clinicians have observed a significant decrease in six-month mortality (p<0.001) among patients with amyloid light-chain (AL) amyloidosis, according to a study published in Blood by researchers at the Mayo Clinic in Rochester, Minnesota. This was true for patients who underwent autologous hematopoietic cell transplantation (AHCT; p=0.07) and those who did not (p<0.001).

“For 40 years, six-month mortality was fixed at approximately 40 percent,” wrote the authors, led by Eli Muchtar, MD, from the Division of Hematology at the Mayo Clinic. “For the first time, however, we have observed a reduction in six-month mortality from 36 percent to 24 percent.”

The researchers analyzed data from 1,551 patients (median age = 63 years; range = 55-70 years) with biopsy-proven systemic AL amyloidosis who were seen at the Mayo Clinic within 90 days of diagnosis, between January 1, 2000, and December 31, 2014. Most patients (63%) were male, and 44 percent of patients were ≥65 years of age.

Patients were excluded from the analysis if they were previously treated for AL amyloidosis or multiple myeloma, had AL amyloidosis because of a lymphoproliferative disorder, or had incidental amyloid deposits in bone marrow/fat tissue without demonstrable visceral involvement.

Patients were divided into three cohorts based on the year of their diagnosis:

  • cohort 1: 2000-2004 (n=422, 27%)
  • cohort 2: 2005-2009 (n=604, 39%)
  • cohort 3: 2010-2014 (n=525, 34%)

Trends in diagnosis revealed that patients diagnosed after 2010 (cohort 3) were:

  • older (age ≥65 years = 48% vs. 41% [cohort 2] vs. 44% [cohort 1]; p=0.01)
  • more likely to be seen within 30 days of diagnosis (67% vs. 58% vs. 64%; p=0.004)
  • less likely to have extensive organ involvement (defined as >2 involved organs; 15% vs. 24% vs. 20%; p<0.001)
  • more likely to have lower rates of cardiac (71% vs. 59% vs. 76%; p=0.01) and liver (16% vs. 22% vs. 27%; p<0.001) involvement
  • more likely to have less renal involvement (59% vs. 66% vs. 58%; p=0.01)

Rates of AHCT were similar across time periods – with approximately one-third of patients undergoing AHCT – but transplant patients in cohort 3 were less likely to have >1 involved organ (40% vs. 49% [cohort 2] vs. 3% [cohort 1]; p=0.05), more likely to receive induction prior to AHCT (38% vs. 19% vs. 29%; p<0.0001), and more likely to have AHCT conditioning with melphalan (82% vs. 60% vs. 61%; p<0.001). The duration of pre-AHCT induction changed over time, with a median of three cycles in cohort 3, compared with two cycles in both cohorts 1 and 2 (p<0.001).

Among patients who did not receive AHCT, firstline treatment choice changed over time. Melphalan/prednisone was the most commonly used in cohort 1 (64%), but its use fell to just 3 percent of patients in cohort 2, with melphalan/dexamethasone becoming the most common regimen (79%). In cohort 3, melphalan/dexamethasone use decreased to 31 percent, with bortezomib-based therapies gaining traction (65%).

Overall, the proportion of patients who achieved a very good partial response (VGPR) or better to firstline therapy was higher in cohorts 3 and 2, compared with cohort 1 (66% vs. 58% vs. 51%; p=0.001). However, rates of complete response did not improve across the three cohorts (36% vs. 36% vs. 29%; p=0.22). Notably, responses of VGPR or better in transplant patients did not change significantly over time (77% vs. 70% vs. 73%; p=0.42); however, response rates did improve among non-transplant patients (58% vs. 49% vs. 24%; p<0.001).

Six-month mortality decreased progressively with each diagnostic era, from 37 percent in cohort 1 to 25 percent in cohort 2 and 24 percent in cohort 3. This trend was similar among AHCT-treated patients (11% vs. 7% vs. 2%) and non-transplant patients (49% vs. 33% vs. 35%).

Treatment with dexamethasone alone was associated with the highest rates of six-month mortality:

  • AHCT: 6%
  • melphalan/prednisone: 43%
  • melphalan/dexamethasone: 26%
  • bortezomib-based therapy: 31%
  • immunomodulatory drugs: 31%
  • dexamethasone alone: 57%

Factors related to mortality included involvement of ≥2 organs, ≥18 mg/dL difference between involved and uninvolved light chains, and troponin ≥0.035 ng/mL.

Median progression-free survival (PFS) was highest in cohort 3: 16 months versus 11 months in cohort 2 and six months in cohort 1 (p<0.001). Again, transplantation did not significantly affect PFS.

Over a median follow-up of 5.6 years (range = 3.1-8.8 years) for surviving patients, two-year OS rates were 60 percent in cohort 3, 54 percent in cohort 2, and 42 percent in cohort 1, whereas four-year OS rates were 54 percent, 42 percent, and 31 percent, respectively (p<0.001 for all comparisons).

Four-year OS was the only measurement of response in which transplantation improved outcome compared with no transplant: 91 percent in cohort 3, 73 percent in cohort 2, and 65 percent in cohort 1, compared with 38 percent, 32 percent, and 16 percent, respectively (p<0.001).

“Our data would suggest that improvements [in survival] relate to a growing availability of effective treatment and potentially better baseline disease characteristics resulting from earlier diagnosis,” Dr. Muchtar and colleagues concluded. “With greater awareness of the disease and additional new drugs to target bone marrow plasma cells and potentially the amyloidosis deposits, we anticipate that comparable advances will be made in successive decades as well.”

The study is limited by its retrospective design and use of data from just one institution, which may affect its generalizability.


Reference

Muchtar E, Gertz MA, Kumar SK, et al. Improved outcomes for newly diagnosed AL amyloidosis over the years 2000-2014: cracking the glass ceiling of early death. Blood. 2017 January 26. [Epub ahead of print]

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